Method for the preparation of citalopram

ABSTRACT

The present invention relates to a method for the preparation of citalopram by alkylation of a 1-(4-fluorophenyl)-1,3-dihydroisobenzofurane derivative.

[0001] This application is a continuation of International applicationno. PCT/DK01/00168, filed Mar. 13, 2001. The prior application is herebyincorporated by reference in its entirety.

[0002] The present invention relates to a method for the preparation ofthe well-known antidepressant drug citalopram,1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile.

BACKGROUND OF THE INVENTION

[0003] Citalopram is a well-known antidepressant drug that has now beenon the market for some years and has the following structure:

[0004] It is a selective, centrally acting serotonin(5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly havingantidepressant activities. The antidepressant activity of the compoundhas been reported in several publications, eg. J. Hyttel Prog.Neuro-Psychopharmacol. & Biol. Psychiat. 1982, 6, 277-295 and A. GravemActa Psychiatr. Scand. 1987, 75, 478-486. The compound has further beendisclosed to show effects in the treatment of dementia andcerebrovascular disorders, EP-A-474580.

[0005] Citalopram was first disclosed in DE 2,657,013, corresponding toU.S. Pat. No. 4,136,193. This patent publication describes thepreparation of citalopram by one method and outlines a further method,which may be used for preparing citalopram.

[0006] According to the process described, the corresponding1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofurancarbonitrile is reactedwith 3-(N,N-dimethylamino)propyl-chloride in the presence ofmethylsulfinylmethide as condensing agent. The starting material wasprepared from the corresponding 5-bromo derivative by reaction withcuprous cyanide.

[0007] International patent application No. WO 98/019511 discloses aprocess for the manufacture of citalopram wherein a (4-(cyano,alkyloxycarbonyl oralkylaminocarbonyl)-2-hydroxy-methylphenyl-(4-fluorophenyl)methanolcompound is subjected to ring closure. The resulting 5-(alkyloxycarbonyl oralkylaminocarbonyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran isconverted to the corresponding 5-cyano derivative and the 5-cyanoderivative is then alkylated with a (3-dimethylamino)propylhalogenide inorder to obtain citalopram.

[0008] It has now, surprisingly, been found that citalopram may bemanufactured by a novel favourable process where5-cyano-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran is alkylated with acompound which may be converted to a dimethylaminopropyl group.

[0009] The alkylation process according to the invention is particularlyadvantageous because the formation of by-products by polymerisation ofthe alkylating agent is avoided whereby a reduction in the amount ofalkylating reagent to be used is made possible. The process of theinvention provides high yields.

SUMMARY OF THE INVENTION

[0010] Thus, the present invention relates to a method for thepreparation of citalopram comprising reaction of a compound of formula(I)

[0011] wherein Y is a group which may be converted to cyano, with acompound having the formula

[0012] wherein X is a suitable leaving group and R is —CH₂—O—Pg,—CH₂—NPg₁Pg₂, —CH₂—NMePg₁, —CO—N(CH₃)₂, —CH(A¹R²)(A²R²), COOR³,—CH₂—CO—NH₂, —CH═CH—R⁷ or —CONHR⁸, wherein Pg is a protection group foran alcohol group, Pg₁ and Pg₂ are protection groups for an amino group,R¹ and R² are independently selected from alkyl, alkenyl, alkynyl andoptionally alkyl substituted aryl and aralkyl groups or R¹ and R²together form a chain of 2 to 4 carbon atoms, R³ and R⁷ areindependently selected from alkyl, alkenyl, alkynyl and optionally alkylsubstituted aryl and aralkyl, R⁸ is hydrogen or methyl and A¹ and A² areselected from O and S;

[0013] to form a compound of the formula

[0014] wherein R and Y are as defined above, followed by, in eitherorder, conversion of the group R to a dimethylaminomethyl group andconversion of the group Y to a cyano group, followed by isolation of thecitalopram base or a pharmaceutically acceptable acid addition saltthereof.

[0015] Thus, in one embodiment, the invention relates to a method forthe preparation of citalopram wherein the compound of formula (I) isreacted with a compound of formula (II) wherein R is —CH₂—O—Pg to form acompound of formula

[0016] wherein Y is a group which may be converted to cyano and Pg is aprotection group for an alcohol group, optionally followed by conversionof the group Y to a cyano group; and thereafter removal of theprotecting group to form a compound of formula

[0017] wherein Y¹ is cyano or a group which may be converted to cyano,and if Y¹ is not cyano, optionally followed by conversion of the groupY¹ to a cyano group; thereafter conversion of the alcohol group to afeasible leaving group, followed by, in either order, conversion of agroup Y¹ which is not cyano to cyano, and replacement of the leavinggroup with a dimethylamino group by reaction with

[0018] a) dimethylamine or a salt thereof,

[0019] b) methylamine followed by methylation or reductive amination, or

[0020] c) with an azide followed by reduction to form the correspondingamine and thereafter methylation or reductive amination.

[0021] In a second embodiment, the invention relates to a method for thepreparation of citalopram wherein the compound of formula (I) is reactedwith a compound of formula (II) wherein R is —CO—N(CH₃)₂ to form acompound of the formula

[0022] wherein Y is as defined above, optionally followed by conversionof the group Y to a cyano group; and thereafter reduction of theresulting compound to form a compound of formula

[0023] wherein Y¹ is cyano or a compound which may be converted tocyano, and if Y¹ is not cyano conversion of the group Y¹ in the compoundof formula (VII) to a cyano group.

[0024] In a third embodiment, the invention relates to a method for thepreparation of citalopram wherein the compound of formula (I) is reactedwith a compound of formula (II) wherein R is —CH₂—N(Pg₁)(Pg₂) to form acompound of formula

[0025] wherein Y is a group which may be converted to a cyano group andPg₁ and Pg₂ are protection groups for an amino group, optionallyfollowed by conversion of the group Y to a cyano group; and thereafterremoval of the protecting groups to form a compound having the formula

[0026] wherein Y¹ is a cyano group or a group which may be converted toa cyano group, followed by, in either order, conversion of a group Y¹which is not cyano to a cyano group and methylation or reductiveamination of the free amino group to form citalopram.

[0027] In a fourth embodiment, the invention relates to a process forthe preparation of citalopram wherein a compound of formula (I) isreacted with a compound of formula (II) wherein R is —CH(A¹R¹)(A²R²) toform a compound of the formula

[0028] wherein Y is a group which may be converted to a cyano group, R¹and R² are independently selected from alkyl, alkenyl, alkynyl andoptionally alkyl substituted aryl and aralkyl groups or R¹ and R²together form a chain of 2 to 4 carbon atoms, and A¹ and A² are selectedfrom O and S; optionally followed by conversion of the group Y to acyano group; and thereafter deprotection of the compound of formula (X)to form a compound of formula

[0029] wherein Y¹ is cyano or a group which may be converted to a cyanogroup and A¹ are as defined above, followed by, in either order,reductive amination with dimethylamine of the compound of formula (XI)and if Y¹ is not cyano, conversion of the group Y¹ to form a cyanogroup.

[0030] In a fifth embodiment, the invention relates to a method for thepreparation of citalopram wherein a compound of formula (I) is reactedwith a compound of formula (II) wherein R is —COOR³ to form a compoundof the formula

[0031] wherein Y is a group which may be converted to cyano and R³ isselected from alkyl, alkenyl, alkynyl and optionally alkyl substitutedaryl and aralkyl, optionally followed by conversion of Y to a cyanogroup; and thereafter

[0032] i) reduction to form an alcohol of formula

[0033]  wherein Y¹ is cyano or a group which may be converted to cyano,and if Y¹ is not cyano, optionally followed by conversion of the groupY¹ to a cyano group; and thereafter conversion of the alcohol group to afeasible leaving group, followed by, in either order, conversion of agroup Y¹ which is not cyano to cyano, and replacement of the leavinggroup with a dimethylamino group by reaction with

[0034] a) dimethylamine or a salt thereof,

[0035] b) methylamine followed by methylation or reductive amination, or

[0036] c) with an azide followed by reduction to form the correspondingamine and thereafter methylation or reductive amination, or

[0037] ii) reaction of a compound of formula (XII) with an amine offormula NH(Me)₂, NH₂Me or NH₃ or a salt thereof to form an amide,followed by, in either order, reduction of the amide, and if Y¹ is notcyano, conversion of the group Y¹ to cyano, and if necessary methylationor reductive amination to form a dimethylamino group.

[0038] In a sixth embodiment, the invention relates to a method for thepreparation of citalopram wherein a compound of formula (I) is reactedwith a compound of formula (II) wherein R is —CH₂—CO—NH₂ to form acompound of the formula

[0039] wherein Y is as defined above, optionally followed by conversionof Y to a cyano group; and thereafter treatment with a hypohalide toform a compound of formula

[0040] wherein Y¹ is a cyano group or a group which may be converted toa cyano group, followed by, in either order, conversion of a group Y¹which is not cyano to a cyano group and methylation or reductiveamination of free amino group to form citalopram.

[0041] In a seventh embodiment, the invention relates to a method forthe preparation of citalopram wherein a compound of formula (I) isreacted with a compound of formula (II) wherein R is —CH═CH—R⁷ to form acompound of the formula

[0042] wherein Y is a group which may be converted to a cyano group andR⁷ is alkyl, alkenyl, alkynyl and optionally alkyl substituted aryl andaralkyl as defined above, optionally followed by conversion of the groupY to a cyano group; and thereafter oxidation to form a compound offormula

[0043] wherein Y¹ is cyano or a group which may be converted to a cyanogroup, followed by, in either order, reductive amination withdimethylamine and if Y¹ is not cyano conversion of the group Y¹ to acyano group to form citalopram.

[0044] In another embodiment, the invention relates to a method for thepreparation of citalopram from a compound of formula

[0045] wherein Y¹ is a cyano group, or a group which can be converted toa cyano group and R² is —CH₂—W, wherein W is a leaving group, or R² iscyano or —CH₂N(CH₃)₂ comprising, in either order, conversion of thegroup Y¹ which is not cyano to a cyano group and conversion of the groupR² which is not —CH₂N(CH₃)₂ to a dimethylaminomethyl group, followed byisolation of citalopram base or a pharmaceutically acceptable acidaddition salt thereof.

[0046] According to this method, a group R² which is —CH₂—W, wherein Wis a leaving group may be converted to a dimethylaminomethyl group byreaction with

[0047] a) dimethylamine or a salt thereof,

[0048] b) methylamine followed by methylation or reductive amination, or

[0049] c) an azide followed by reduction to form the corresponding amineand thereafter methylation or reductive amination.

[0050] Further, according to this method a group R² which is cyano maybe converted to a dimethylaminomethyl group by reduction followed bymethylation or reductive amination of the free amino group formed.Reduction of the cyano group to an amino group may be carried out usingusing Rh, Raney Ni etc. as a catalyst.

[0051] The compound of formula (XVI) may be prepared by reaction of acompound of formula

[0052] wherein Y¹ is a cyano group, or a group which can be converted toa cyano group, with a compound of formula

[0053] wherein X is a leaving group and R² is —CH₂—W, wherein W is aleaving group, or R² is cyano or —CH₂N(CH₃)₂; provided R² is not—CH₂N(CH₃)₂ when X is halogen and Y¹ is cyano, and if Y¹ is not cyano,optionally followed by conversion of the group Y¹ to a cyano group.

[0054] In a further embodiment, the invention relates to a method forthe preparation of citalopram wherein a compound of formula (I) isreacted with a compound of formula (II) wherein R is —CH₂—NMe(Pg₁) toform a compound of formula

[0055] wherein Y is a group which may be converted to a cyano group andPg₁ is a protection group for an amino group, optionally followed byconversion of the group Y to a cyano group; and thereafter removal ofthe protection group to form a compound of formula

[0056] wherein Y¹ is a cyano group or a group which may be converted tocyano, followed by, in either order, conversion of the group Y¹ which isnot cyano to a cyano group and methylation or reductive amination of theamino group to form citalopram.

[0057] In still another embodiment, the invention relates to a processfor the preparation of citalopram wherein a compound of formula (I) isreacted with a compound of formula (II) wherein R is —CO—NHR⁸ to form acompound of formula

[0058] wherein Y is a group which may be converted to cyano and R⁸ ishydrogen or methyl, optionally followed by conversion of the group Y toa cyano group; and thereafter reduction to form a compound of theformula

[0059] wherein Y¹ is cyano or a group which may be converted to cyanoand R⁸ is hydrogen or methyl followed by, in either order, methylationor reductive amination to form the dimethylamino group and if Y¹ is notcyano, conversion of Y¹ to cyano.

[0060] In a further embodiment, the invention relates to a method forthe preparation of citalopram comprising reaction of a compound offormula (Ia) with a compound of formula (II) wherein R is—C(A¹R⁴)(A²R⁵)(A³R⁶) to form a compound of the formula

[0061] wherein Y¹ is a cyano group or a group which may be converted tocyano and wherein each of R⁴, R⁵ and R⁶ are independently selected fromalkyl, alkenyl, alkynyl and optionally alkyl substituted aryl andaralkyl and A¹, A² and A³ is selected from O and S, and if Y¹ is notcyano optionally followed by conversion of Y¹ to a cyano group; andthereafter hydrolysis to form a compound of formula

[0062] wherein Y¹ is cyano or a group which may be converted to cyano,and A¹ and A² is as defined above and if Y¹ is not cyano, optionallyconversion of Y¹ to cyano; and followed by

[0063] i) reduction of a compound of formula (XXII) or an ester thereofto form an alcohol of formula

[0064]  wherein Y¹ is cyano or a group which may be converted to cyano,and if Y¹ is not cyano, optionally followed by conversion of the groupY¹ to a cyano group; and thereafter conversion of the alcohol group to afeasible leaving group, followed by, in either order, conversion of agroup Y¹ which is not cyano to cyano, and replacement of the leavinggroup with a dimethylamino group by reaction with

[0065] a) dimethylamine or a salt thereof,

[0066] b) methylamine followed by methylation or reductive amination, or

[0067] c) with an azide followed by reduction to form the correspondingamine and thereafter methylation or reductive amination, or

[0068] ii) conversion of a compound of formula (XXII) to an amide withan amine of formula NH(Me)₂, NH₂Me, NH₃ or a salt thereof, followed by,in either order, reduction of the amide, and if Y¹ is not cyano,conversion of the group Y¹ to cyano, and if necessary methylation orreductive amination to form a dimethylamino group.

[0069] The invention also relates to the intermediates having theformula (III), (XXI) and (XXII) and intermediates having the formula(V), (VII), (IX), (XVI), (XVIII) and (XI) wherein Y¹ is a group whichmay be converted to cyano.

[0070] In yet another aspect, the present invention relates to anantidepressant pharmaceutical composition comprising citaloprammanufactured by the process of the invention.

[0071] The alkylation step where the compound of formula (I) and (Ia)are reacted with a compound of formula (II) and (IIa), respectively, issuitably carried out by treatment of the compound of formula (I) and(Ia) with a base such as for example LDA ( lithiumdiisopropylamine),LiHMDS (hexamethyldisilasan lithium), NaH, NaHMDS (hexamethyldisilasansodium) and metalalkoxides such as NaOMe, KOMe, LiOMe, NaOtertBu,KOtertBu and LiOtertBu in an aprotic organic solvent such as THF(tetrahydrofuran), DMF (dimethylformamide), NMP (N-methylpyrrolidon),ethers such as diethylether or dioxalane, toluene, benzene, or alkanesand mixtures thereof. The anion formed is then reacted with a compoundof formula (II) or (IIa) whereby a group of formula —CH₂—CH₂—R and—CH₂—CH₂—R² is introduced into position 1 of the isobenzofuranyl ringsystem.

[0072] The reaction of the compound of formula (I) and (Ia) and with acompound of formula (II) and (IIa), respectively, is suitably carriedout under non-aqueous conditions.

[0073] Suitable leaving groups X and W, may be a halogenide, or asulphonate of formula —O—SO₂—R⁰ wherein R⁰ is alkyl, aralkyl, aryl oraryl substituted with alkyl. Conventionally, R⁰ is methyl orp-methylphenyl.

[0074] Groups Y¹ which can be converted to a cyano group may be selectedfrom halogen, —O—SO₂—(CF)_(n)—CF₃, wherein n is 0-8, —CHO, —COOR′,—CONR′R″, —NHR′″wherein R′ and R″ are hydrogen, alkyl, alkenyl oralkynyl, or optionally alkyl substituted aryl or aralkyl and R′″ ishydrogen or alkylcarbonyl or Y is an an oxazoline or thiazoline group ofthe formula

[0075] wherein

[0076] U is O or S;

[0077] R¹²-R¹³ are each independently selected from hydrogen and alkyl,or R¹² and R¹³ together form a C₂₋₅ alkylene chain thereby forming aspiro ring; R¹⁰ is selected from hydrogen and alkyl, R¹¹ is selectedfrom hydrogen, alkyl, a carboxy group or a precursor group therefore, orR¹⁰ and R¹¹ together form a C₂₋₅ alkylene chain thereby forming a spiroring.

[0078] Y may be any other group, which can be converted to a cyanogroup.

[0079] The substituents R¹, R², R³, R⁴, R⁵ and R⁶ are preferably alkylor aralkyl. Suitably, R¹ and R² and R⁴, R⁵ and R⁶ are identical.

[0080] The alcohol protecting group, Pg, may be a trialkylsilyl group, abenzyl group or a tetrahydropyranyl group (THP).

[0081] According to the invention, the alcohol protecting group isremoved to form the compound of formula (IV) using conventional methodsfor removal of the protection group in question.

[0082] Thus, where the protecting group is trialkylsilyl the protectinggroup may be removed by treatment with a base, an organic or mineralacid or a flouride such as KF, or trialkylaminoflouride.

[0083] Where Pg is benzyl, the protecting group may be removed byreduction using Pd/C or Pt/C as a catalyst.

[0084] Where Pg is a tetrahydropyranyl (THP) group, the protecting groupmay be removed by treatment with an organic or mineral acid, or resinscarrying H⁺ groups such as Dowex H′ or Amberlyst.

[0085] The alcohol group in the compound of formula (V) is converted toa feasible leaving group such as halogen, or a sulphonate of formula—O—SO₂—R⁰ wherein R⁰ is as defined above, by reaction with reagents suchas thionylchloride, mesylchloride, tosylchloride etc.

[0086] The resulting compound is then reacted with dimethylamine or asalt thereof, e.g. M⁺, N(CH₃)₂ wherein M⁺ is Li⁺ or Na⁺. The reaction issuitably carried out in an aprotic organic solvent such as THF(tetrahydrofuran), DMF (dimethylformamide), NMP (N-methyl pyrrolidon),ethers such as diethylether, or dioxalane, toluene, benzene, or alkanesand mixtures thereof. The compound of formula (V) carrying a suitableleaving group may also be converted to citalopram by reaction withdimethylammonium chloride in presence of a base. Alternatively, thecompound of formula (V) carrying a suitable leaving group, such as asulphonate of formula —O—SO₂—R⁰ wherein R⁰ is as defined above, may bereacted with an azide, such as sodium azide, followed by reduction usingPd/C as a catalyst to form a compound of formula (IX) and thereaftermethylation or reductive amination to form Citalopram.

[0087] The compound of formula (V) carrying a suitable leaving group,may also be converted to citalopram by reaction with methylaminefollowed by methylation or reductive amination to form a dimethylaminogroup.

[0088] In a compound of formula (XVI) wherein R² is —CH₂—W wherein W isa suitable leaving group, W may be replaced by a dimethylamino group asdescribed above.

[0089] The reduction of the amides of formula (VI) and (XIX) isconveniently carried out in toluene using Red-Al as a reducing agent.

[0090] Suitable groups Pg₁ and Pg₂ are aralkyl or —SO₂—R⁰ groups whereinR⁰ is as defined above, typically benzyl or tosyl, or Pg₁ and Pg₂together with the N atom to which they are attached form an optionallysubstituted phthalimide group.

[0091] The protecting groups, Pg₁ and Pg₂, may be removed usingconventional methods for removal of such protective groups. Thephthalimide groups may thus be converted to an amino group by treatmentwith hydrazin or methylamine and ethanol.

[0092] Where the protecting group is an aralkyl group, such as benzyl,it may be removed by reduction, typically in presence of Pd/C or Pt/C asa catalyst.

[0093] Protecting groups of formula —SO₂—R⁰ may be removed by treatmentwith Red-Al.

[0094] The amino group in the compounds of formula (IX), (XVIII) and(XX) may be methylated with methylating agents such as MeI and Me₂SO₄,wherein Me is methyl. The methylation is carried out using conventionalprocedures for carrying out such reactions.

[0095] Alternatively, citalopram is formed by reductive amination.According to this procedure, the compound of formula (IX), (XVIII) or(XX) is reacted with compounds such as formaldehyde, paraformaldehyde ortrioxan in the presence of a reducing agent such as NaBH₄ or NaBH₃CN.The reductive amination is carried out using conventional procedures forcarrying out such reactions.

[0096] The compound of formula (Xa) or (Xb) may suitably be converted tothe corresponding aldehyde by treatment with an organic or mineral acidor with resins carrying H⁺ groups such as Dowex H⁺ or Amberlyst.

[0097] The resulting aldehyde may be converted to citalopram byreductive amination, i.e. by reaction with dimethylamine in presence ofa reducing agent such as NaBH₄ or NaBH₃CN.

[0098] The aldehydes of formula (XV) may be converted to a dimethylaminogroup by analogous methods.

[0099] The ester derivative of formula (XII) may be converted tocitalopram via the corresponding alcohol of formula (V) by reduction ofthe ester using Red-Al as a reducing agent or via an amide by reactionof the ester with an amine, preferably NH₂(Me)₂ or a salt thereof. Thereduction of the amide may suitably be carried out in toluene usingRed-Al as reducing agent. Conversion of a free amino group or amonomethylamino group to a dimethylamino group may be carried out asdescribed above.

[0100] Suitably, the agent useful for conversion of a compound offormula (XIII) to a compound of formula (IX) is NaOH/Br₂.

[0101] Oxidation of the compound of formula (XIV) may be carried out bytreatment of the compound with ozone in a polar solvent such as alcohol,water, acetic acid or esters thereof. Alternatively, the compound offormula (XIV) may be treated with oxidation agents such as NaIO₄,OsO₄/NaIO₄ and KMnO₄.

[0102] Hydrolysis of a compound of formula (XXI) to form a compound offormula (XXII) may be carried out using mineral acids or organic acids.

[0103] Conversion of the compound of formula (XXII) to an alcohol offormula (V) or an amide may suitably be carried out via thecorresponding acid chloride. The acid chloride may be prepared bytreatment of the acid with POCl₃, PCl₅ or SOCl₂ neat or in a suitablesolvent, such as toluene or toluene comprising a catalytic amount ofN,N-dimethylformamide. The ester is obtained by treatment of the acidwith an alcohol, in the presence of an acid, preferably a mineral acidor a Lewis acid, such as HCl, H₂SO₄, POCl₃, PCl₅ or SOCl₂.Alternatively, the ester may be obtained from the acid chloride byreaction with an alcohol. The ester or the acid chloride is thenconverted to an amide of by amidation with ammonia or an alkylamine,preferably t-butyl amine.

[0104] The conversion to amide may also be obtained by reaction of theester with ammonia or an alkylamine under pressure and heating.

[0105] The processes for the conversion of the corresponding alcohol oramide to the dimethylamino group of citalopram have already beendescribed above.

[0106] When Y is halogen or CF₃—(CF₂)_(n)—SO₂—O—, wherein n is 0-8, theconversion to a cyano group may be carried out by reaction with acyanide source, for example KCN, NaCN, CuCN, Zn(CN)₂ or (R¹⁵)₄NCN, where(R¹⁵)₄ indicates four groups, which may be the same or different, andare selected from hydrogen and straight chain or branched alkyl, in thepresence of a palladium catalyst and a catalytic amount of Cu⁺ or Zn²⁺,or with Zn(CN)₂ in the presence of a palladium catalyst. The conversionof a compound wherein Y is halogen or CF₃—(CF₂)_(n)—SO₂—O—, wherein n is0-8, by reaction with a cyanide source in the presence of a palladiumcatalyst, may be carried out as described in WO 0013648.

[0107] When Y is Cl or Br the conversion to a cyano group may also becarried out by reaction with a cyanide source, for example KCN, NaCN,CuCN, Zn(CN)₂ or (R¹⁵)₄NCN, where (R¹⁵)₄ indicates four groups, whichmay be the same or different, and are selected from hydrogen andstraight chain or branched alkyl, in the presence of a nickel catalyst.The conversion of a compound wherein Y is halogen orCF₃—(CF₂)_(n)—SO₂—O—, wherein n is 0-8, by reaction with a cyanidesource in the presence of a nickel catalyst may be carried out asdescribed in WO 00/11926.

[0108] The reactions may be performed in any convenient solvent asdescribed in Sakakibara et. al. Bull. Chem. Soc. Jpn. 1988, 61,1985-1990. Preferred solvents are acetonitrile, ethylacetate, THF, DMFor NMP.

[0109] When Y is an oxazoline or a thiazoline of the formula (VI), theconversion to a cyano may be carried out as described in WO 00/23431.

[0110] When Y is CHO, the conversion to a cyano group may be carried outby conversion of the formyl group to an oxime or similar group byreaction with a reagent R¹⁶—V—NH₂, wherein R¹⁶ is hydrogen, alkyl, arylor heteroaryl and V is O, N or S, followed by dehydration with a commondehydrating agent, for example thionylchloride, aceticanhydride/pyridine, pyridine/HCl or phosphor pentachloride. Preferredreagents, R¹⁶—V—NH₂, are hydroxylamine and compounds wherein R¹⁶ isalkyl or aryl and V is N or O.

[0111] When Y is —COOH, the conversion to a cyano group may be carriedout via the corresponding acid chloride or ester and amide.

[0112] The acid chloride is conveniently obtained by treatment of theacid with POCl₃, PCl₅ or SOCl₂ neat or in a suitable solvent, such astoluene or toluene comprising a catalytic amount ofN,N-dimethylformamide. The ester is obtained by treatment of the acidwith an alcohol, in the presence of an acid, preferably a mineral acidor a Lewis acid, such as HCl, H₂SO₄, POCl₃, PCl₅ or SOCl₂.Alternatively, the ester may be obtained from the acid chloride byreaction with an alcohol. The ester or the acid chloride is thenconverted to an amide by amidation with ammonia or an alkylamine,preferably t-butyl amine.

[0113] The conversion to amide may also be obtained by reaction of theester with ammonia or an alkylamine under pressure and heating.

[0114] The amide group is then converted to a cyano group bydehydration. The dehydrating agent may be any suitable dehydratingagent, and the optimal agent may easily be determined by a personskilled in the art. Examples of suitable dehydrating agents are SOCl₂,POCl₃ and PCl₅, preferably SOCl₂.

[0115] In a particularly preferred embodiment, the carboxylic acid isreacted with an alcohol, preferably ethanol, in the presence of POCl₃,in order to obtain the corresponding ester, which is then reacted withammonia thereby giving the corresponding amide, which in turn is reactedwith SOCl₂ in toluene comprising a catalytic amount ofN,N-dimethylformamide.

[0116] Alternatively, a compound where Y is —COOH may be reacted withchlorosulfonyl isocyanate in order to form the nitrile, or treated witha dehydrating agent and a sulfonamide as described in WO 0044738.

[0117] When Y is —NHR′″, where R′″ is hydrogen, the conversion intocyano is preferably performed by diazotation and followed by reactionwith CN⁻. Most preferably NaNO₂ and CuCN and/or NaCN is used. When R′″is alkylcarbonyl, the compound is initially subjected to hydrolysisthereby obtaining the corresponding compound wherein R′″ is H, which isthen converted as described above. The hydrolysis may be performedeither in acidic or basic environment.

[0118] Starting materials of formula (I) wherein X is halogen may beprepared as described in GB 1526331, compounds of formula (I) wherein Xis —O—SO₂—(CF₂)_(n)—CF₃ may be prepared analogously to the compoundsdescribed in WO 99/00640, compounds of formula (I) wherein X is anoxazoline or a thiazoline group may be prepared analogous to thecompounds described in WO 0023431, compounds wherein X is formaldehydemay be prepared analogously to the compounds described in WO 99/30548,compounds wherein X is —COOH, and esters and amides thereof may beprepared analogously to the compounds described in WO 98/19511 andcompounds of formula I wherein is —NHR′″ may be prepared analogously tothe compounds described in WO 98/19512.

[0119] The reaction conditions, solvents, etc. used for the reactionsdescribed above are conventional conditions for such reactions and mayeasily be determined by a person skilled in the art.

[0120] The starting material of formula (Ia) wherein Y¹ is a cyano groupmay be prepared as described in U.S. Pat. No. 4,136,193 or as describedin WO 98/019511.

[0121] The compounds of formula (II) and (IIa) are commerciallyavailable or may be prepared form commercially available startingmaterials using conventional techniques.

[0122] Citalopram is on the market as an antidepressant drug in the formof the racemate. However, in the near future the active S-enantiomer ofcitalopram is also going to be introduced to the market.

[0123] S-citalopram may be prepared by separation of the opticallyactive isomers by chromatography.

[0124] Throughout the specification and claims, the term alkyl refers toa branched or unbranched alkyl group having from one to six carbon atomsinclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl,2-methyl-2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl.

[0125] Similarly, alkenyl and alkynyl, respectively, designate suchgroups having from two to six carbon atoms, including one double bondand triple bond respectively, such as ethenyl, propenyl, butenyl,ethynyl, propynyl, and butynyl.

[0126] The term aryl refers to a mono- or bicyclic carbocyclic aromaticgroup, such as phenyl and naphthyl, in particular phenyl.

[0127] The term aralkyl refers to aryl-alkyl, wherein aryl and alkyl isas defined above.

[0128] The term optionally alkyl substituted aryl or aralkyl means aryland aralkyl as above which are optionally substituted with one or morealkyl groups. Halogen means chloro, bromo or iodo.

[0129] Citalopram may be used as the free base, preferably incrystalline form, or as a pharmaceutically acceptable acid addition saltthereof. As acid addition salts, such salts formed with organic orinorganic acids may be used. Exemplary of such organic salts are thosewith maleic, fumaric, benzoic, ascorbic, succinic, oxalic,bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic,propionic, tartaric, salicylic, citric, gluconic, lactic, malic,mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic,glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophyllineacetic acids, as well as the 8-halotheophyllines, for example8-bromotheophylline. Exemplary of such inorganic salts are those withhydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitricacids.

[0130] The acid addition salts of the compounds may be prepared bymethods known in the art. The base is reacted with either the calculatedamount of acid in a water miscible solvent, such as acetone or ethanol,with subsequent isolation of the salt by concentration and cooling, orwith an excess of the acid in a water immiscible solvent, such asethylether, ethylacetate or dichloromethane, with the salt separatingspontaneously.

[0131] The pharmaceutical compositions of the invention may beadministered in any suitable way and in any suitable form, for exampleorally in the form of tablets, capsules, powders or syrups, orparenterally in the form of usual sterile solutions for injection.

[0132] The pharmaceutical formulations of the invention may be preparedby conventional methods in the art. For example, tablets may be preparedby mixing the active ingredient with ordinary adjuvants and/or diluentsand subsequently compressing the mixture in a conventional tablettingmachine. Examples of adjuvants or diluents comprise: Corn starch, potatostarch, talcum, magnesium stearate, gelatine, lactose, gums, and thelike. Any other adjuvant or additive, colourings, aroma, preservativesetc. may be used provided that they are compatible with the activeingredients.

[0133] Solutions for injections may be prepared by solving the activeingredient and possible additives in a part of the solvent forinjection, preferably sterile water, adjusting the solution to thedesired volume, sterilising the solution and filling it in suitableampoules or vials. Any suitable additive conventionally used in the artmay be added, such as tonicity agents, preservatives, antioxidants, etc.

[0134] The invention is further illustrated by the following examples.

EXAMPLE 1

[0135] A solution of1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (4.8 g, 0.02mol) in THF (50 ml) was added dropwise to a solution of LDA ( Butyllithium 1.6 M (15 mL), disopropylamine 2.6 g) at −30° C. under anatmosphere of nitrogen. After stirring at −30° C. for 10 minutes, asolution of a compound of formula (II) or (IIa) ( 0.02 mol) in THF (25mL) was added dropwise and allowed to warm to room temperature andstirred for a further 60 minutes. The reaction was then quenched withice, extracted with toluene (3×50 mL), washed with water (50 mL) andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel using mixtures of n-heptane/EtOAc as theeluent.

1. A method for the preparation of citalopram comprising reacting acompound of formula (I)

wherein Y is a group which may be converted to cyano, with a compoundhaving the formula

wherein X is a suitable leaving group and R is —CH₂—O—Pg, —CH₂—NPg₁Pg₂,—CH₂—NMePg₁, —CO—N(CH₃)₂, —CH(A¹R¹)(A²R²), —COOR³, —CH₂—CO—NH₂,—CH═CH—R⁷ or —CONHR⁸, wherein Pg is a protection group for an alcoholgroup, Pg₁ and Pg₂ are protection groups for an amino group, R¹ and R²are independently selected from alkyl, alkenyl, alkynyl and optionallyalkyl substituted aryl or aralkyl groups or R¹ and R² together form achain of 2 to 4 carbon atoms, each of R³ and R⁷ are independentlyselected from alkyl, alkenyl, alkynyl and optionally alkyl substitutedaryl or aralkyl, R⁸ is hydrogen or methyl and A¹ and A² are selectedfrom O and S; to form a compound of formula

wherein R and Y are as defined above, followed by, in either order,converting R to a dimethylaminomethyl group and converting Y to a cyanogroup, followed by isolating citalopram base or a pharmaceuticallyacceptable acid addition salt thereof.
 2. The method according to claim1 wherein the compound of formula (I) is reacted with a compound offormula (II) wherein R is —CH₂—O—Pg to form a compound of formula

wherein Y is a group which may be converted to cyano and Pg is aprotection group for an alcohol group, optionally followed by convertingY to a cyano group; followed by removing the protecting group to form acompound of formula

wherein Y¹ is cyano or a group which may be converted to cyano, and ifY¹ is not cyano, optionally followed by converting Y¹ to a cyano group;and thereafter converting the alcohol group to a feasible leaving group,followed by, in either order, converting Y¹ which is not cyano to cyano,and replacing the leaving group with a dimethylamino group by reactingwith a) dimethylamine or a salt thereof, b) methylamine followed bymethylation or reductive amination, or c) with an azide followed byreduction to form the corresponding amine and thereafter methylation orreductive amination.
 3. The method according to claim 1 wherein thecompound of formula (I) is reacted with a compound of formula (II)wherein R is —CO—N(CH₃)₂ to form a compound of the formula

wherein Y is as defined above, optionally followed by converting Y to acyano group; and thereafter reducing the resulting compound to form acompound of formula

wherein Y¹ is cyano or a compound which may be converted to cyano, andif Y¹ is not cyano converting Y¹ in the compound of formula (VII) tocyano.
 4. The method according to claim 1 wherein the compound offormula (I) is reacted with a compound of formula (II) wherein R is—CH₂—N(Pg₁)(Pg₂) to form a compound of formula

wherein Y is a group which may be converted to a cyano group and Pg₁ andPg₂ are protection groups for an amino group, optionally followed byconverting Y to a cyano group; and thereafter by removing the protectinggroups to form a compound having the formula

wherein Y¹ is a cyano group or a group which may be converted to a cyanogroup, followed by, in either order, converting Y¹ which is not cyano toa cyano group and methylation or reductive amination of the free aminogroup to form citalopram.
 5. The method according to claim 1 wherein acompound of formula (I) is reacted with a compound of formula (II)wherein R is —CH(A¹R¹)(A²R²) to form a compound of the formula

wherein Y is a group which may be converted to a cyano group, R¹ and R²are independently selected from alkyl, alkenyl, alkynyl and optionallyalkyl substituted aryl and aralkyl groups or R¹ and R² together form achain of 2 to 4 carbon atoms and A¹ and A² are selected from O and S;optionally followed by converting Y to a cyano group; and thereafterdeprotecting the compound of formula (X) to form a compound of formula

wherein Y¹ is cyano or a group which may be converted to a cyano groupand A¹ is as defined above, followed by, in either order, by reductiveamination with dimethylamine of the compound of formula (XI) and if Y¹is not cyano, converting Y¹ to form a cyano group.
 6. The methodaccording to claim 1 wherein a compound of formula (I) is reacted with acompound of formula (II) wherein R is —COOR³ where R³ is as definedabove to form a compound of the formula

wherein Y is a group which may be converted to cyano and R³ is selectedfrom alkyl, alkenyl, alkynyl and optionally alkyl substituted aryl andaralkyl, optionally followed by converting Y to a cyano group; andthereafter i) reduction to form an alcohol of formula

 wherein Y¹ is cyano or a group which may be converted to cyano, and ifY¹ is not cyano, optionally followed by converting Y¹ to a cyano group;and thereafter converting the alcohol group to a feasible leaving group,followed by, in either order, converting Y¹ which is not cyano to cyano,and replacing the leaving group with a dimethylamino group by reactionwith a) dimethylamine or a salt thereof, b) methylamine followed bymethylation or reductive amination, or c) with an azide followed byreduction to form the corresponding amine and thereafter methylation orreductive amination, or ii) reacting the compound of formula (XII) withan amine of NH(Me)₂, NH₂Me, NH₃ or a salt thereof to form an amide,followed by, in either order, reducing the amide, and if Y¹ is notcyano, converting the group Y¹ to cyano, and if necessary methylation orreductive amination to form a dimethylamino group.
 7. The methodaccording to claim 1 wherein a compound of formula (I) is reacted with acompound of formula (II) wherein R is —CH₂—CO—NH₂ to form a compound ofthe formula

wherein Y is as defined above, optionally followed by converting Y to acyano group; followed by treating the resulting compound with ahypohalide to form a compound of formula

wherein Y¹ is a cyano group or a group which may be converted to a cyanogroup, followed by, in either order, converting Y¹ which is not cyano toa cyano group and methylation or reductive amination of free amino groupto form citalopram.
 8. The method according to claim 1 wherein acompound of formula (I) is reacted with a compound of formula (II)wherein R is —CH═CH—R⁷ to form a compound of the formula

wherein Y is a group which may be converted to a cyano group and R⁷ isalkyl, alkenyl, alkynyl and optionally alkyl substituted aryl andaralkyl as defined above, optionally followed by converting Y to a cyanogroup; and thereafter oxidizing the resulting compound to form acompound of formula

wherein Y¹ is cyano or a group which may be converted to a cyano group,followed by, in either order, reductive amination with dimethylamine andif Y¹ is not cyano, converting Y¹ to a cyano group to form citalopram.9. A method for the preparation of citalopram from a compound of formula

wherein Y¹ is a cyano group, or a group which can be converted to acyano group and R² is —CH₂—W, wherein W is a leaving group, or R² iscyano or —CH₂N(CH₃)₂ comprising, in either order, converting Y¹ which isnot cyano to a cyano group and converting the group R² which is not—CH₂N(CH₃)₂ to a dimethylaminomethyl group, followed by isolatingcitalopram base or a pharmaceutically acceptable acid addition saltthereof.
 10. The method according to claim 9 wherein R² is —CH₂—W,wherein W is a leaving group and the group W is replaced by adimethylaminomethyl group by reacting with a) dimethylamine or a saltthereof, b) methylamine followed by methylation or reductive amination,or c) with an azide followed by reduction to form the correspondingamine and thereafter methylation or reductive amination.
 11. The methodaccording to claim 9 wherein group R² is cyano which is converted to adimethylaminomethyl group by reduction followed by methylation orreductive amination of the free base of the amino group formed.
 12. Themethod according to claim 9 wherein the compound of formula (XVI) isprepared by reacting a compound of formula

wherein Y¹ is a cyano group, or a group which can be converted to acyano group, with a compound of formula

wherein X is a leaving group and R² is —CH₂—W, wherein W is a leavinggroup, or R² is cyano or —CH₂N(CH₃)₂; provided that R² is not—CH₂N(CH₃)₂ when X is halogen and Y¹ is cyano; and if Y¹ is not cyano,optionally followed by converting Y¹ to a cyano group.
 13. The methodaccording to claim 1 wherein the compound of formula (I) is reacted witha compound of formula (II) wherein R is —CH₂—NMe(Pg₁) to form a compoundof formula

wherein Y is a group which may be converted to a cyano group and Pg₁ isa protection group for an amino group, optionally followed by convertingY to a cyano group; thereafter removing the protection group to form acompound of formula

wherein Y¹ is a cyano group or a group which may be converted to cyano,followed by, in either order, converting Y¹ which is not cyano to acyano group and methylation or reductive amination of the amino group toform citalopram.
 14. The method according to claim 1 wherein thecompound of formula (I) is reacted with a compound of formula (II)wherein R is —CO—NHR⁸ to form a compound of formula

wherein Y is a group which may be converted to cyano and wherein R⁸ ishydrogen or methyl, optionally followed by converting Y to a cyanogroup; and thereafter reducing the resulting compound to form a compoundof the formula

wherein Y¹ is cyano or a group which may be converted to cyano and R⁸ ishydrogen or methyl, followed by, in either order, methylation orreductive amination to form a dimethylamino group, and if Y¹ is notcyano converting Y¹ to a cyano group.
 15. A method for the preparationof citalopram, comprising reacting a compound of formula (Ia) with acompound of formula (II) wherein R is —C(A¹R⁴)(A²R⁵)(A³R⁶) to form acompound of the formula

wherein Y¹ is a cyano group or a group which may be converted to cyanoand wherein each of R⁴, R⁵ and R⁶ are independently selected from alkyl,alkenyl, alkynyl and optionally alkyl substituted aryl and aralkyl andA¹, A² and A³ are selected from O and S, if Y¹ is not cyano optionallyfollowed by converting Y¹ to a cyano group; and thereafter hydrolysis toform a compound of formula

wherein Y¹ is cyano or a group which may be converted to cyano, and A¹and A² are as defined above and if Y¹ is not cyano, optionally followedby converting Y¹ to cyano; and followed by i) reducing a compound offormula (XXII) or an ester thereof to form a compound of formula

 wherein Y¹ is cyano or a group which may be converted to cyano, and ifY¹ is not cyano, optionally followed by converting group Y¹ to a cyanogroup; and thereafter converting the alcohol group to a feasible leavinggroup, followed by, in either order, converting Y¹ which is not cyano tocyano, and replacing the leaving group with a dimethylamino group byreaction with a) dimethylamine or a salt thereof, b) methylaminefollowed by methylation or reductive amination, or c) with an azidefollowed by reduction to form the corresponding amine and thereaftermethylation or reductive amination, or ii) converting the compound offormula (XXII) or an ester thereof to an amide followed by, in eitherorder, reducing the amide, and if Y¹ is not cyano, Y¹ to cyano, and ifnecessary methylation or reductive amination to form a dimethylaminogroup.
 16. A compound of the formula

wherein Y is a group which may be converted to cyano and R is —CH₂—O—Pg,—CH₂—NPg₁Pg₂, —CH₂—NMePg₁, —CO—N(CH₃)₂, —CH(A¹R¹)(A²R²), —COOR³,—CH₂—CO—NH₂, —CH═CH—R⁷ or —CONHR⁸, wherein Pg is a protection group foran alcohol group, Pg₁ and Pg₂ are protection groups for an amino group,R¹ and R² are independently selected from alkyl, alkenyl, alkynyl andoptionally alkyl substituted aryl or aralkyl groups or R¹ and R²together form a chain of 2 to 4 carbon atoms, each of R³ and R⁷ areindependently selected from alkyl, alkenyl, alkynyl and optionally alkylsubstituted aryl or aralkyl, R⁸ is hydrogen or methyl and A¹ and A² areselected from O and S; or an acid addition salt thereof.
 17. A compoundof formula

wherein Y¹ is a group which may be converted to cyano, or an acidaddition salt thereof.
 18. A compound of formula

wherein Y¹ is a compound which may be converted to cyano, or an acidaddition salt thereof.
 19. A compound of formula

wherein Y¹ is a group which may be converted to a cyano group, or anacid addition salt thereof.
 20. A compound of formula

wherein Y¹ is a group which may be converted to a cyano group and A¹ isO or S, or an acid addition salt thereof.
 21. A compound of formula

wherein Y¹ is a group which may be converted to a cyano group and R² is—CH₂—W, wherein W is a leaving group or R² is cyano or —CH₂N(CH₃)₂, oran acid addition salt thereof.
 22. A compound of formula

wherein Y¹ is a group which may be converted to cyano, or an acidaddition salt thereof.
 23. A compound of formula

wherein Y¹ is a cyano group or a group which may be converted to cyanoand wherein each of R⁴, R⁵ and R⁶ are independently selected from alkyl,alkenyl, alkynyl and optionally alkyl substituted aryl and aralkyl andA¹ , A² and A³ are selected from O and S, or an acid addition saltthereof.
 24. A compound of formula

wherein Y¹ is cyano or a group which may be converted to cyano, and A¹and A² is selected from O and S, or an acid addition salt thereof.